N-alkyl piperidyl alkyl esters of diphenyl acetic acid and 9-fluorenyl carboxylic acid



Patented Aug. 19, 1952 N-A-LIKYL PIPER "Chicago, Ill., a ss Skokie. Ill.,"a corporation ofilllinois No Drawing; Application i 10, i947, Serial No. 740,712-' j 1 y 9 Claims. (01. zen-494.3):

This invention relates to piperidylalkyl esters of diarylacetic acids. In particular it relates to piperidylalkylesters of aromatic substituted acetic acids having the general formula:

whereinthenitrogen-containing ring; is complete- 1y saturated; Alk represents a lower alkylene radical such as methylene, ethylene, propylene,

trimethylene and the butylene radicals; Ar and Ar' represent simply a'rylra dicals such as ph'enyl,

tolyl, halophenyl. anisyl, naphthyl, xenyland the like; R representsya lower alkyl "radical 1 suc h as methyl, ethyl, pro yl or'bu'tyli' and R'jrepresents hydrogen or lower alkyl. A -an Arf togethercan form an arylerie radical such asthe o piphenylene radical, which together witnith'e grouping comprises a Q-fiuorenyl radical; Otherjarylene radicals which are within the ',.purvi'ew :of this invention include those; which together: with the Cl'lf'groupgmake. u lo -xanthyl, IO-thioxanthyl and 9,10-dihydro-ranthryl' radicals. As used herein, the term diaryl includes two 'ary1 radicals or one arylene radical.

The following substances'are illustrative of our invention. They are prepared by treatment of the N alkylpiperidylalkan'ols with i diarylacetyl halides in inert media. (A) 2 (6,N dimethyl 2 piperidybethyl diphenylacetate, which has the formula 7 CH3 CH2 CuHs CHa-CH C'H'CHzCH2O'C0'- CH I CuHs (B) 3-(N-ethyl-alpha piperidyhpropylphenyltolylacetate, having the formula 45s PATENT oFFicE a;s07,777 v .i-'D'YL ALKYL EsTE-ns 10F 51.11- PHENYL'AGET-ICAGID, AND

onrmoxymc ACID I V Robert RlifButtnerQSkokie,and John-MJBr'oWn. v

ignors toGrD. Searle'& (30a v d'n mec-nm xan the'ne lo-oarboiryla e, of v (D) r-N 'ethm' etaebip tidy ineliylfthioxan- 'thene-lo-carboitylate,which has the formula 0 ongc'm o d' n (E) '2-0:-etnyi-a1 ha.iiietnynbeta pipendyl ethyli9;10=dihydroanthracne; the formula ca iOl The compounds which comprisethis invention :are useful in therapeutics, particularly as anti: spasmodic agents. The esters are prepared by esterifying an N-alkylpiperidylalkanol with a diarylacetic acid or preferably with a diarylacetyl chloride. The N-alkyl-piperidylalkanols are.synthesized from the corresponding pyridylalkanolsr The latter are hydrogenated, preferably in the presence of platinum oxide catalyst, to piperidy1-' .alkanols, which are then alkylated by any of 'a variety of alkylation procedures, such as treat- I ment with an alkyl halide, reduction in the presence of an aliphatic aldehyde and the like.

The amino esters readily form salts with common inorganic and organic acids, and these salts are generally readily water-soluble. Among the acids which are suitable for this purpose are hydrochloric, hydrobromic, sulfuric, phosphoric, citric, tartaric, acetic and other similar acids which provide non-toxic anions. These salts are generally crystalline solids having the same therapeutic properties as the bases from which 1 they are derived and constitute a preferred form of these compounds. It will be understood that the appended claims include the free basic esters as well as the salts thereof. The following examples are intended merely, to illustrate our invention and do not limit it in spirit or .in scope.

Example 1 To a solution of 34.5 g. of diphenylacetyl chloride in ml. of dry benzene is added a solution of 20.1 g. of 2-(N-methyl-gamma-piperidyl) ethanol (prepared by catalytic reduction of Z-(gamma-pyridyl) ethanol in the presence of platinum oxide, and subsequent methylation; B. P. C. at 1.5 mm.; 17. 1.4746) in 100 ml. of benzene. The resulting mixture is heated on the steam bath for five hours. Following the heating period, 100 .ml.- more ,Of benzene is added and the mixture is made alkaline by shaking with a solution of 16 g. of sodium hydroxide in 200 ml. of water. The benzene layer is sep- 50 arated and the aqueous rafilnate extracted with 200 ml. of fresh benzene. The combined extracts '4 are washed with water, dried over sodium sulfate and filtered. Subsequent removal of solvent on the water bath at 60 C. under water pump vacuum leaves a dark oily residue.

The residue is taken up in 510 ml. of dry ether and treated with charcoal, and a small amount of insoluble material is filtered out. Upon addition of the theoretical amount of absolute alcoholic hydrochloric acid, the hydrochloride is precipitated as well-defined white? crystals. The

crystals are washed by decantation with dry I ether, recovered on a Biichner funnel, washed additionally thereon and dried in vacuo over :sodium hydroxide; M. P. 168-170 C. Upon recrystallization from isopropanol and ethyl acetate (1:1), treating with charcoal in process,

there are obtained colorless crystals of 2-(N- methyl-gamma-piperidyl) ethyl diphenylacetate hydrochloride of,M. P. 171l72 C. The free ester has the formula v CeHs CHzCH2-OC 0-CH CH on, CH,

l 1 CH2 C 2 Example 2 excess dilute sodium hydroxide and the organic layer" separated. The aqueous layeris extracted 'With benzene and the extract. iscombined with the organic layer. The resulting benzene solutionis washed with water, dried and evaporated, yielding oily 3-.(N-wethyl-gamma-piperidyl) propyl 9,10edihydroanthracene-9-carboxylate. The hydrochloride of this ester is prepared by treating thedry ethereal solution of-the ester with an equivalent of absolute alcoholic hydrogen chloride.

Example 3' By following the methods of the above examples there may be prepared the following esters:

Percent E t g' g Nitrogen 5 er chl oride,

Calcd. Found i f if 2-(N-Methyl-alpha-piperidyl)ethyl diphenylacetate-.. 152-153 -.2-(l;1-%Vlethy1-a1pha-pipe1idy1)ethyl fluorene-Q-carbox- 3.77 3.34

1 y a e. 1- (11V JWIethyI-aIphaiperidyI) -2-propy1 fluorene-9-car- 3. 63 3. 43

oxy e. 1-gN-Methyl-alpha-piperidyl)-2-propyl diphenylacef 3. 61 3.76 v a e. 3-gob?Methyl-alpha-piperidyl)-l-propy1 diphenylace- 103-105 Q a e. 3-gl-lvleghyl-alpha-piperidyl)-l-propy1 fluorene-Q-ear- 3. 63 3. 19

oxy a e. 2-gl-lviethyl-gamma-piperidyl)ethyl fluorene-Q-csr- 3. 77- 3.34 I oxy e. ,v

- 3-%Nt-Methyl-gamma-piperidyl)-1-pr0pyldiphenylace -111 a e. 3-(N-Methyl-gamma-piperidyl)-l-propyl fluorene-9- 3; 63 3.38

carboxylate;

We claim: 1. A member of the group consisting of a basic ester and acid addition salts thereof, said basic ester having the formula wherein the nitrogen-containing ring is completely saturated, R is a member of the group consisting of hydrogen and lower alkyl radicals, R is a lower alkyl radical, Alk is a lower alkylene radical, and X is a member of the group consisting of 9-fluorenyl and diphenylmethyl radicals.

2. An acid addition salt of a basic ester of the formula wherein the nitrogen-containing ring is completely saturated, R is a lower alkyl radical, and Alk is a lower alkylene radical.

3. An acid addition salt of a basic ester of the formula wherein the nitrogen-containing ring is completely saturated and R. is a lower alkyl radical. 4. An acid addition salt of a basic ester of the N/ OHa wherein the nitrogen-containing ring is completely saturated.

5. The hydrochloride of the basic ester of claim 4.

6. An acid addition salt of a basic ester of the formula wherein the nitrogen-containing ring is completely saturated, R is a lower alkyl radical and Alk is a lower alkylene radical. I

7. An acid addition salt of a basic ester of the formula v ozHi-o-oo-ofl I Q R wherein the nitrogencontaining ring is completely saturated and R is a lower alkyl radical. 8. An acid addition salt of a basic ester of the formula wherein the nitrogen-containing ring is completely saturated.

9. The hydrochloride of the basic ester of claim 8.

ROBERT R. BURTNER. JOHN M. BROWN.

, REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,079,962 Miescher May 11, 1937 2,143,491 Miescher Jan. 10, 1939 2,221,828 Wolfes Nov. 19, -1940 2,229,533 Walter Jan. 21, 1941 2,377,040 Rieveschl May 29, 1945 2,387,879 Burtner Oct. 30, 1945 OTHER REFERENCES Burtner: J. Amer. Chem. Soc. (1943), pp. 262-267.

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1. A MEMBER OF THE GROUP CONSISTING OF A BASIC ESTER AND ACID ADDITION SALTS THEREOF, SAID BASIC ESTER HAVING THE FORMULA 